Regulation of proinflammatory cytokines gene expression by nociceptin/orphanin FQ in the spinal cord and the cultured astrocytes
ABSTRACT Peripheral inflammation induces central sensitization characterized by the development of allodynia and hyperalgesia to thermal stimuli. Recent evidence suggests that activation of glial cells and a subsequent increase in proinflammatory cytokines contribute to the development of behavioral hypersensitivity after nerve injury or peripheral inflammation. The neuropeptide nociceptin/orphanin FQ (N/OFQ), the endogenous agonist of the N/OFQ peptide receptor (ORL1 receptor), has been demonstrated to play an important role in modulation of nociceptive signals. In the present study, we investigated: (1) astrocyte activation and proinflammatory cytokine expression at the lumbar spinal cord following intraplantar administration of complete Freund's adjuvant (CFA) in rats; (2) the mechanism of N/OFQ on nociception modulation, the relationship between N/OFQ and cytokines in the rat CNS in vivo and in vitro. The results showed: (1) CFA-induced peripheral inflammation evoked robust astrocyte activation and proinflammatory cytokines spinally; (2) down-regulation of cytokine mRNA transcripts by intrathecal administration of N/OFQ, the effects produced by N/OFQ were abolished by combination with ORL1 receptor-specific antagonist [Nphe(1)]N/OFQ(1-13)NH2; (3) ORL1 receptor was expressed on astrocytes of rat spinal cord; (4) cytokine gene expression was inhibited in astrocyte cultures exposed to N/OFQ, the inhibiting effects of N/OFQ were significantly blocked by [Nphe(1)]N/OFQ(1-13)NH2. The present data demonstrated that astrocyte activation and enhanced cytokine expression at the CNS had a role in eliciting behavioral hypersensitivity; the anti-nociception function of N/OFQ might be dependent on cytokines derived from astrocytes, the effects were attributable to the ORL1 receptor pathway.
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- "The NOP was demonstrated to be expressed not only on neurons but also on astrocytes and microglia  , which further suggest the involvement of these cells in the modulation of N/OFQ system. Fu et al. have  shown that spinal cord astrocyte activation and in vitro cytokine production by those glial cells are attenuated by N/OFQ through the astrocytic NOP. It was shown that LPS-induced IL-1í µí»½ gene expression was reduced by N/OFQ in cultured primary microglia, but it was enhanced in neuronal cultures . "
ABSTRACT: Nociceptin/orphanin FQ (N/OFQ) antinociception, which is mediated selectively by the N/OFQ peptide receptor (NOP), was demonstrated in pain models. In this study, we determine the role of activated microglia on the analgesic effects of N/OFQ in a rat model of neuropathic pain induced by chronic constriction injury (CCI) to the sciatic nerve. Repeated 7-day administration of minocycline (30 mg/kg i.p.), a drug that affects microglial activation, significantly reduced pain in CCI-exposed rats and it potentiates the analgesic effects of administered N/OFQ (2.5-5 μg i.t.). Minocycline also downregulates the nerve injury-induced upregulation of NOP protein in the dorsal lumbar spinal cord. Our in vitro study showed that minocycline reduced NOP mRNA, but not protein, level in rat primary microglial cell cultures. In [(35)S]GTPγS binding assays we have shown that minocycline increases the spinal N/OFQ-stimulated NOP signaling. We suggest that the modulation of the N/OFQ system by minocycline is due to the potentiation of its neuronal antinociceptive activity and weakening of the microglial cell activation. This effect is beneficial for pain relief, and these results suggest new targets for the development of drugs that are effective against neuropathic pain.BioMed Research International 09/2014; 2014:762930. DOI:10.1155/2014/762930 · 2.71 Impact Factor
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- "Such cellular infiltrates may further contribute to the concentration of local neuron-derived OFQ/N, since neutrophils are known to produce OFQ/N (Fiset et al., 2003). Finally, as detailed below, astrocytes express NOP-R and cytokine production by astrocytes can be inhibited by OFQ/N, an effect which represents one mechanism by which OFQ/N may reduce pain sensitivity (Fu et al., 2007b). "
ABSTRACT: The neuropeptide, orphanin FQ/nociceptin (OFQ/N or simply, nociceptin), is expressed in both neuronal and nonneuronal tissue, including the immune system. In the brain, OFQ/N has been investigated in relation to stress, anxiety, learning and memory, and addiction. More recently, it has also been found that OFQ/N influences glial cell functions, including oligodendrocytes, astrocytes and microglial cells. However, this latter research is relatively small, but potentially important, when observations regarding the relationship of OFQ/N to stress and emotional functions is taken into consideration and integrated with the growing evidence for its involvement in cells that mediate inflammatory events. This review will first provide an overview and understanding of how OFQ/N has been implicated in the HPA axis response to stress, followed by an understanding of its influence on natural and learned anxiety-like behavior. What emerges from an examination of the literature is a neuropeptide that appears to counteract anxiogenic influences, but paradoxically, without attenuating HPA axis responses generated in response to stress. Studies utilized both central administration of OFQ/N, which was shown to activate the HPA axis, as well as antagonism of NOP-R, the OFQ/N receptor. In contrast, antagonist or transgenic OFQ/N or NOP-R knockout studies, showed augmentation of HPA axis responses to stress, suggesting that OFQ/N may be needed to control the magnitude of the HPA axis response to stress. Investigations of behavior in standard exploratory tests of anxiogenic behavior (eg., elevated plus maze) or learned fear responses have suggested that OFQ/N is needed to attenuate fear or anxiety-like behavior. However, some discrepant observations, in particular, those that involve appetitive behaviors, suggest a failure of NOP-R deletion to increase anxiety.Frontiers in Cellular Neuroscience 10/2013; 7:173. DOI:10.3389/fncel.2013.00173 · 4.18 Impact Factor
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- "N/OFQ and NOP receptor are expressed on lymphocytes, monocytes, and peripheral blood mononuclear cells and in T cell and B cell lines, where they modulate synthesis and release of neuromodulators (Halford et al., 1995; Wick et al., 1995; Peluso et al., 1998; Arjomand et al., 2002). N/OFQ blocks synthesis of proinflammatory cytokines in the spinal cord, astrocytes, and splenocytes (Fu et al., 2007; Miller and Fulford, 2007) and inhibits Complete Freund's adjuvant-induced increase in proinflammatory interleukin-6, interleukin-1b, and tumor necrosis factor–a mRNA in cultured astrocytes (Fu et al., 2007). N/OFQ-NOP receptor interactions also induce neutrophil chemotaxis (Fiset et al., 2003; Serhan et al., 2001), block antibody formation in vivo and in vitro in rodent spleen cells (Anton et al., 2010), and inhibit T cell function (Waits et al., 2004). "
ABSTRACT: The Nociceptin/Orphanin FQ (N/OFQ) peptide (NOP) receptor is the fourth and most recently discovered member of the opioid receptor superfamily that also includes μ, δ and κ opioid receptor subtypes (MOR, DOR and KOR, respectively). The widespread anatomical distribution of the NOP receptor enables the modulation of several physiological processes by its endogenous agonist, N/OFQ. Accordingly, the NOP receptor has gained a lot of attention as a potential target for the development of ligands with therapeutic utility in several pathophysiological states. NOP receptor activation frequently results in effects opposing classical opioid receptor action, therefore regulation of the NOP receptor and conditions affecting its modulatory tone are important to understand. Mounting evidence illustrates a heterologous interaction of the NOP receptor with other G protein-coupled receptors, including MOR, DOR and KOR, which may subsequently influence their function. Our focus in this review is to summarize and discuss the findings that delineate the cellular mechanisms of NOP receptor signaling and regulation as well as the regulation of other receptors by N/OFQ and the NOP receptor.Molecular pharmacology 02/2013; 83(5). DOI:10.1124/mol.112.084632 · 4.12 Impact Factor